Elucidating the mechanism of ERbeta in colon carcinogenesis

描述（由申请人提供）：目前还不存在针对结肠癌的真正预防性或靶向治疗。然而，女性激素替代治疗意外地降低了结直肠癌的风险，口服避孕药的使用与这种疾病的发病率降低有关，雌二醇已被证明可以减少结肠癌前病变的形成。雌激素受体β（ER））是人类结肠上皮中的主要雌激素受体;该基因的多态性与结肠癌发病率相关，并且其在肿瘤中的缺失与晚期Dukes分期和较差的存活率相关。体内小鼠研究表明，ER <$激动剂治疗可预防肠道肿瘤的发展，ER <$的缺失可导致结肠腺瘤的增加。总的来说，这些观察结果清楚地指出了ER在结直肠癌中的保护作用。雌激素受体对健康和疾病有重要影响。它们可以被配体激活或失活，并且是治疗靶向的理想候选物。存在选择性激活ER <$的化合物，避免雌激素通过ER <$激活在男性和女性中诱导的不良影响。作为ER？作为结肠癌治疗的靶点具有重要的潜力，理解其作用的基本机制背景并鉴定其活性的生物标志物是至关重要的。PI的初步数据支持ER在结肠中发挥这些作用的三种关键机制的存在。这三种机制是1）预测的ER β和PROX 1相互作用，2）通过抑制NF κ B/IL-6信号传导的抗炎反应和3）通过调节miRNA介导的途径（包括miR-17 -92和miR-200 a/B簇）的抗致癌作用。该项目利用核受体和细胞信号传导中心的技能，详细了解ER在结肠癌预防和治疗中的作用和潜力。本项目的总体目标是为利用雌激素受体预防和治疗新型科洛癌提供机制基础。

DESCRIPTION (provided by applicant): A truly preventive or targeted therapy against colon cancer does not yet exist. However, hormone replacement therapy in women unexpectedly resulted in reduced risk of colorectal cancer, use of oral contraceptives is associated with a lower incidence of this disease, and estradiol has been shown to reduce the formation of preneoplastic lesions in the colon. Estrogen receptor beta (ER¿) is the predominant estrogen receptor in the human colonic epithelium; polymorphisms in this gene are related to colon cancer incidence and its loss in tumors is related to advanced Dukes staging and poorer survival. In vivo mouse studies have demonstrated that ER¿ agonist treatment prevents intestinal tumor development and that deletion of ER¿ leads to an increase in colon adenomas. Collectively, these observations clearly point to a protective role for ER¿ in colorectal cancer. Estrogen receptors have significant consequences in health and diseases. They can be activated or inactivated by ligands, and are ideal candidates for therapeutic targeting. Compounds exist that selectively activate ER¿, circumventing the adverse effects that estrogen induces in men and women through ER¿ activation. As ER¿ hold significant potential as a target for colon cancer therapy, it is essential to understand the basic mechanistic background of its action and to identify biomarkers of its activity. The PI's preliminary data supports the existence of three critical mechanisms whereby ER¿ exerts these effects in the colon. These three mechanisms are 1) a predicted ER¿ and PROX1 interaction, 2) an anti---inflammatory response via repression of NFkB/IL-6 signaling and 3) anti---oncogenic effects through the regulation of miRNA mediated pathways, including the miR17-92 and miR-200a/b clusters. This project takes advantage of the skills of the Center for Nuclear Receptors and Cell Signaling to provide a detailed understanding of ER¿'s role and potential in colon cancer prevention and treatment. The overall objective of this project is to provide the mechanistic basis for novel colo cancer prevention and therapy utilizing ER¿.